Drug abuse has become a major social and medical problem around the world. Presently, it is estimated that there are over 2 million drug users in the USA. Clinical studies have reported that one of the major problems confronted by substance abusers during periods of abstinence is their susceptibility to "cravings" for the drug that may arise in an environment associated with drug use. In addition, behavioral studies have shown that drug-related cues can acquire reinforcing properties through classical conditioning. However, little is known about the biological basis of cure elicited drug craving. One of the main goals of neurobiological research is to study the different neural systems and molecular mechanisms involved in drug dependence. The nucleus accumbens is part of the ventral striatum, and the medial prefrontal cortex have previously been implicated in mediating the motor activation and reinforcing effects of psychostimulant drugs such as cocaine. In addition, studies have demonstrated that several neuropeptides such as neurotensin and chlocystokinin (CCK) are co-localized with dopamine within these mesolimbic structures and their actions may modulate psychostimulant reward. Furthermore, recent molecular studies reveal that accumbal neurons show changes in the activity or expression of several cellular proteins as well as synaptic remodeling following chronic exposure to cocaine administration. Although these recent findings report long-term cellular and neurochemical changes within the brain during cocaine- seeking behavior, not much is known about the underlying molecular mechanisms and neuropeptide modulation of environmentally-elicited cocaine seeking behavior. The current proposal seeks to investigate the role of neurotensin and CCK within the nucleus accumbens and medial pre-frontal cortex in the acquisition and expression of environment- elicited cocaine seeking behavior. In addition, the present experiments will further study gene expression within these two mesolimbic structures induced by the reinstatement of cocaine-seeking behavior. The two major goals of the proposed experiments are: 1) to investigate the role of neurotensin and CCK receptors within the nucleus accumbens subregions and ventral and dorsal areas of the medial prefrontal cortex in mediating reinstatement of cocaine seeking behavior. 2) to characterize possible gene candidates involved in the expression of environmentally-elicited cocaine seeking behavior using microarray technology. Results from the proposed research plan may provide new knowledge on the neurochemical substrates and genetic expression involved in the control of cocaine-seeking behavior.